tbuckley/cabot-search huggingface dataset:
Sodium–Glucose Cotransporter 2 Inhibitor Treatment and Risk of Atrial Fibrillation: Scandinavian Cohort Study
Authors: Arvid Engström, Viktor Wintzell, Mads Melbye, Anders Hviid, Björn Eliasson, Soffia Gudbjörnsdottir, Kristian Hveem, Christian Jonasson, Henrik Svanström, Björn Pasternak, Peter Ueda
Journal: Diabetes Care (2022)

OBJECTIVE To assess the association between use of sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of new-onset atrial fibrillation (AF) in routine clinical practice. RESEARCH DESIGN AND METHODS We used nationwide registers in Denmark, Norway, and Sweden from 2013 to 2018 in order to include patients without a history of AF who were newly prescribed an SGLT2 inhibitor or an active comparator (glucagon-like peptide 1 [GLP-1] receptor agonist). We performed a cohort study to assess new-onset AF in intention-to-treat analyses using Cox regression, adjusted for baseline covariates with propensity score weighting. RESULTS We identified 79,343 new users of SGLT2 inhibitors (59.2% dapagliflozin, 40.0% empagliflozin, 0.8% canagliflozin, &amp;lt;0.1% ertugliflozin) and 57,613 new users of GLP-1 receptor agonists. Mean age of the study cohort was 61 years and 60% were men. The adjusted incidence rate of new-onset AF was 8.6 per 1,000 person-years for new users of SGLT2 inhibitors compared with 10.0 per 1,000 person-years for new users of GLP-1 receptor agonists. The adjusted hazard ratio (aHR) was 0.89 (95% CI 0.81–0.96), and the rate difference was 1.4 fewer events per 1,000 person-years (95% CI 0.6–2.1). Using an as-treated exposure definition, the aHR for new-onset AF was 0.87 (95% CI 0.76–0.99). No statistically significant heterogeneity of the aHRs was observed between subgroups of patients with and without a history of heart failure or major cardiovascular disease. CONCLUSIONS In this cohort study using nationwide data from three countries, use of SGLT2 inhibitors, compared with GLP-1 receptor agonists, was associated with a modestly reduced risk of new-onset AF.
13. Older Adults: <i>Standards of Care in Diabetes—2023</i>
Authors: Nuha A. ElSayed, Grazia Aleppo, Vanita R. Aroda, Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer, Billy S. Collins, Marisa E. Hilliard, Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry, Priya Prahalad, Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Robert A. Gabbay
Journal: Diabetes Care (2022)

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Criteria for Hyperinflammation Developing in <scp>COVID</scp>‐19: Analysis of 2 Cohorts From Different Periods of the Pandemic
Authors: Shirkhan Amikishiyev, M. Guven Gunver, Murat Bektas, Sarvan Aghamuradov, Burak Ince, Nevzat Koca, Ege Sinan Torun, Numune Aliyeva, Selma Sari, Cigdem Cetin, Banu C. Yalcin‐Dulundu, Rabia Deniz, Fatih Kemik, Besim Fazil Agargun, Ubeyde Ayse Gulseren, Beliz Besisik, Onur Alkan, Ceren Bagriacik, Yavuz B. Tor, Naci Senkal, Yunus Catma, Gorkem Durak, Sevim Mese, Ali Agacfidan, Murat Kose, Mustafa Erelel, A. Atahan Cagatay, Serap Simsek‐Yavuz, Sevgi Kalayoglu‐Besisik, Figen Esen, Ahmet Gül
Journal: Arthritis & Rheumatology (2022)

Objective Hyperinflammation (HI) that develops in week 2 of COVID‐19 contributes to a worse outcome. Because week 2 laboratory findings can be relatively mild, the available criteria for classification of hemophagocytic lymphohistiocytosis or macrophage activation syndrome are not helpful. Methods Our study included a discovery cohort of patients from Turkey with symptomatic COVID‐19 who were followed up while hospitalized during the initial wave and a replication cohort of hospitalized patients from a later period, all of whom required oxygen support and received glucocorticoids. Diagnosis of HI was made by an expert panel; most patients with COVID‐19–associated HI (HIC) received tocilizumab or anakinra. Clinical and laboratory data from start day of treatment with tocilizumab or anakinra in HIC patients were compared with the data from day 5–6 in patients without HIC. Values maximizing the sensitivity and specificity of each parameter were calculated to determine criteria items. Results The discovery cohort included 685 patients, and the replication cohort included 156 patients, with 150 and 61 patients receiving treatment for HI, respectively. Mortality rate in HI patients in the discovery cohort (23.3%) was higher than the rate in patients without HI (3.7%) and the rate in patients in the overall replication cohort (10.3%). The 12‐item criteria that we developed for HIC showed that a score of 35 provided 85.3% sensitivity and 81.7% specificity for identification of HIC. In the replication cohort, the same criteria resulted in 90.0% sensitivity for HIC; however, lower specificity values were observed because of the inclusion of milder cases of HIC responding only to glucocorticoids. Conclusion The use of the 12‐item criteria for HIC can better define patients with HIC with reasonable sensitivity and specificity and enables an earlier treatment start. image
Kidney Hemodynamic Effects of Angiotensin Receptor Blockade, Sodium-Glucose Cotransporter-2 Inhibition Alone, and Their Combination: A Crossover Randomized Trial in People With Type 2 Diabetes
Authors: Rosalie A. Scholtes, Anne C. Hesp, Charlotte M. Mosterd, Frank Geurts, Ewout J. Hoorn, Daan J. Touw, Merle M. Krebber, Jaap A. Joles, Hiddo J.L. Heerspink, Daniël H. van Raalte
Journal: Circulation (2022)
The provisional OMERACT ultrasonography score for giant cell arteritis
Authors: Christian Dejaco, Cristina Ponte, Sara Monti, Davide Rozza, Carlo Alberto Scirè, Lene Terslev, George A W Bruyn, Dennis Boumans, Wolfgang Hartung, Alojzija Hočevar, Marcin Milchert, Uffe Møller Døhn, Chetan B Mukhtyar, Markus Aschwanden, Philipp Bosch, Dario Camellino, Stavros Chrysidis, Giovanni Ciancio, Maria Antonietta D’Agostino, Thomas Daikeler, Bhaskar Dasgupta, Eugenio De Miguel, Andreas P Diamantopoulos, Christina Duftner, Ana Agueda, Ulrich Fredberg, Petra Hanova, Ib Tønder Hansen, Ellen-Margrethe Hauge, Annamaria Iagnocco, Nevsun Inanc, Aaron Juche, Rositsa Karalilova, Toshio Kawamoto, Kresten Krarup Keller, Helen Isobel Keen, Tanaz A Kermani, Minna J. Kohler, Matthew Koster, Raashid Ahmed Luqmani, Pierluigi Macchioni, Sarah Louise Mackie, Esperanza Naredo, Berit Dalsgaard Nielsen, Michihiro Ogasawara, Carlos Pineda, Valentin Sebastian Schäfer, Luca Seitz, Alessandro Tomelleri, Karina D Torralba, Kornelis S M van der Geest, Kenneth J Warrington, Wolfgang A Schmidt
Journal: Annals of the Rheumatic Diseases (2022)

To develop an Outcome Measures in Rheumatology (OMERACT) ultrasonography score for monitoring disease activity in giant cell arteritis (GCA) and evaluate its metric properties.The OMERACT Instrument Selection Algorithm was followed. Forty-nine members of the OMERACT ultrasonography large vessel vasculitis working group were invited to seven Delphi rounds. An online reliability exercise was conducted using images of bilateral common temporal arteries, parietal and frontal branches as well as axillary arteries from 16 patients with GCA and 7 controls. Sensitivity to change and convergent construct validity were tested using data from a prospective cohort of patients with new GCA in which ultrasound-based intima-media thickness (IMT) measurements were conducted at weeks 1, 3, 6, 12 and 24.Agreement was obtained (92.7%) for the OMERACT GCA Ultrasonography Score (OGUS), calculated as follows: sum of IMT measured in every segment divided by the rounded cut-off values of IMTs in each segment. The resulting value is then divided by the number of segments available. Thirty-five members conducted the reliability exercise, the interrater intraclass correlation coefficient (ICC) for the OGUS was 0.72-0.84 and the median intrareader ICC was 0.91. The prospective cohort consisted of 52 patients. Sensitivity to change between baseline and each follow-up visit up to week 24 yielded standardised mean differences from -1.19 to -2.16, corresponding to large and very large magnitudes of change, respectively. OGUS correlated moderately with erythrocyte sedimentation rate, C reactive protein and Birmingham Vasculitis Activity Score (corrcoeff 0.37-0.48).We developed a provisional OGUS for potential use in clinical trials.
Network Topology Can Explain Differences in Pleiotropy Between <i>Cis-</i> and <i>Trans</i>-regulatory Mutations
Authors: Pétra Vande Zande, Patricia J Wittkopp
Journal: Molecular Biology and Evolution (2022)

Abstract A mutation's degree of pleiotropy (i.e., the number of traits it alters) is predicted to impact the probability of the mutation being detrimental to fitness. For mutations that impact gene expression, mutations acting in cis have been hypothesized to generally be less pleiotropic than mutations affecting the same gene's expression in trans, suggesting that cis-regulatory mutations should be less deleterious and more likely to fix over evolutionary time. Here, we use expression and fitness data from Saccharomyces cerevisiae gene deletion strains to test these hypotheses. By treating deletion of each gene as a cis-regulatory mutation affecting its own expression and deletions of other genes affecting expression of this focal gene as trans-regulatory mutations, we find that cis-acting mutations do indeed tend to be less pleiotropic than trans-acting mutations affecting expression of the same gene. This pattern was observed for the vast majority of genes in the data set and could be explained by the topology of the regulatory network controlling gene expression. Comparing the fitness of cis- and trans-acting mutations affecting expression of the same gene also confirmed that trans-acting deletions tend to be more deleterious. These findings provide strong support for pleiotropy playing a role in the preferential fixation of cis-regulatory alleles over evolutionary time.
A Phylogenetic Framework to Simulate Synthetic Interspecies RNA-Seq Data
Authors: Paul Bastide, Charlotte Soneson, David B Stern, Olivier Lespinet, Mélina Gallopin
Journal: Molecular Biology and Evolution (2022)

Interspecies RNA-Seq datasets are increasingly common, and have the potential to answer new questions about the evolution of gene expression. Single-species differential expression analysis is now a well-studied problem that benefits from sound statistical methods. Extensive reviews on biological or synthetic datasets have provided the community with a clear picture on the relative performances of the available methods in various settings. However, synthetic dataset simulation tools are still missing in the interspecies gene expression context. In this work, we develop and implement a new simulation framework. This tool builds on both the RNA-Seq and the phylogenetic comparative methods literatures to generate realistic count datasets, while taking into account the phylogenetic relationships between the samples. We illustrate the usefulness of this new framework through a targeted simulation study, that reproduces the features of a recently published dataset, containing gene expression data in adult eye tissue across blind and sighted freshwater crayfish species. Using our simulated datasets, we perform a fair comparison of several approaches used for differential expression analysis. This benchmark reveals some of the strengths and weaknesses of both the classical and phylogenetic approaches for interspecies differential expression analysis, and allows for a reanalysis of the crayfish dataset. The tool has been integrated in the R package compcodeR, freely available on Bioconductor.
8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: <i>Standards of Care in Diabetes—2023</i>
Authors: Nuha A. ElSayed, Grazia Aleppo, Vanita R. Aroda, Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer, Billy S. Collins, Marisa E. Hilliard, Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry, Priya Prahalad, Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Robert A. Gabbay
Journal: Diabetes Care (2022)

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Longitudinal cardio-respiratory fitness prediction through wearables in free-living environments
Authors: Dimitris Spathis, Ignacio Perez-Pozuelo, Tomas I. Gonzales, Yu Wu, Soren Brage, Nicholas Wareham, Cecilia Mascolo
Journal: npj Digital Medicine (2022)

Cardiorespiratory fitness is an established predictor of metabolic disease and mortality. Fitness is directly measured as maximal oxygen consumption (VO
Severe mpox (formerly monkeypox) disease in five patients after recent vaccination with MVA-BN vaccine, Belgium, July to October 2022
Authors: Nicole Berens-Riha, Tessa De Block, Jojanneke Rutgers, Johan Michiels, Liesbeth Van Gestel, Matilde Hens, Chris Kenyon, Emmanuel Bottieau, Patrick Soentjens, Johan van Griensven, Isabel Brosius, Kevin K Ariën, Marjan Van Esbroeck, Antonio Mauro Rezende, Koen Vercauteren, Laurens Liesenborghs
Journal: Eurosurveillance (2022)

Vaccination is important in containing the 2022 mpox (formerly monkeypox) epidemic. We describe five Belgian patients with localised severe symptoms of proctitis and penile oedema, occurring between 4 and 35 days after post-exposure preventive vaccination or after one- or two-dose off-label pre-exposure preventive vaccination with MVA-BN vaccine. Genome sequencing did not reveal evidence for immune escape variants. Healthcare workers and those at risk should be aware of possible infections occurring shortly after vaccination and the need for other preventive measures.
Genome-Wide Association Study Identifies <i>ROBO2</i> as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors
Authors: Xuexia Wang, Purnima Singh, Liting Zhou, Noha Sharafeldin, Wendy Landier, Lindsey Hageman, Paul Burridge, Yutaka Yasui, Yadav Sapkota, Javier G. Blanco, Kevin C. Oeffinger, Melissa M. Hudson, Eric J. Chow, Saro H. Armenian, Joseph P. Neglia, A. Kim Ritchey, Douglas S. Hawkins, Jill P. Ginsberg, Leslie L. Robison, Gregory T. Armstrong, Smita Bhatia
Journal: Journal of Clinical Oncology (2022)

Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication).
Adenine base editor–mediated correction of the common and severe IVS1-110 (G&amp;gt;A) β-thalassemia mutation
Authors: Giulia Hardouin, Panagiotis Antoniou, Pierre Martinucci, Tristan Felix, Sandra Manceau, Laure Joseph, Cécile Masson, Samantha Scaramuzza, Giuliana Ferrari, Marina Cavazzana, Annarita Miccio
Journal: Blood (2022)

β-Thalassemia (BT) is one of the most common genetic diseases worldwide and is caused by mutations affecting β-globin production. The only curative treatment is allogenic hematopoietic stem/progenitor cells (HSPCs) transplantation, an approach limited by compatible donor availability and immunological complications. Therefore, transplantation of autologous, genetically-modified HSPCs is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors are not equally effective in all patients and CRISPR/Cas9 nuclease-based strategies raise safety concerns. Thus, base editing strategies aiming to correct the genetic defect in patients' HSPCs could provide safe and effective treatment. Here, we developed a strategy to correct one of the most prevalent BT mutations (IVS1-110 [G>A]) using the SpRY-ABE8e base editor. RNA delivery of the base editing system was safe and led to ∼80% of gene correction in the HSPCs of patients with BT without causing dangerous double-strand DNA breaks. In HSPC-derived erythroid populations, this strategy was able to restore β-globin production and correct inefficient erythropoiesis typically observed in BT both in vitro and in vivo. In conclusion, this proof-of-concept study paves the way for the development of a safe and effective autologous gene therapy approach for BT.
Overlapping features of therapy-related and de novo <i>NPM1</i>-mutated AML
Authors: Jad Othman, Manja Meggendorfer, Enrico Tiacci, Christian Thiede, Richard Schlenk, Richard Dillon, Sebastian Stasik, Alessandra Venanzi, Sarah Bertoli, Eric Delabesse, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Amanda F. Gilkes, Ian Thomas, Maria Teresa Voso, Alessandro Rambaldi, Lorenzo Brunetti, Vincenzo M. Perriello, Vibeke Andresen, Bjorn T. Gjertsen, Maria Paola Martelli, Christian Récher, Christoph Röllig, Martin Bornhäuser, Hubert Serve, Carsten Müller-Tidow, Claudia D. Baldus, Tortsten Haferlach, Nigel Russell, Brunangelo Falini
Journal: Blood (2022)

NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of "therapy-related" NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.
Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia
Authors: Heikki Kuusanmäki, Olli Dufva, Markus Vähä-Koskela, Aino-Maija Leppä, Jani Huuhtanen, Ida Vänttinen, Petra Nygren, Jay Klievink, Jonas Bouhlal, Petri Pölönen, Qi Zhang, Shady Adnan-Awad, Cristina Mancebo-Pérez, Joseph Saad, Juho Miettinen, Komal K. Javarappa, Sofia Aakko, Tanja Ruokoranta, Samuli Eldfors, Merja Heinäniemi, Kim Theilgaard-Mönch, Ulla Wartiovaara-Kautto, Mikko Keränen, Kimmo Porkka, Marina Konopleva, Krister Wennerberg, Mika Kontro, Caroline A. Heckman, Satu Mustjoki
Journal: Blood (2022)

Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of >500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with erythroid or megakaryocytic differentiation ex vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.